Opioid analgesics are narcotic drugs used for treating a wide variety of clinical symptoms, most particularly pain. The serious drawbacks in the use of plant opioids, such as morphine, including addiction and intestinal blockage, are well known. A form of naturally occurring opiates is found in the nervous tissues of animals. These natural animal opiates are known as enkephalins. Naturally occurring enkephalins, which are part of a larger family of chemical signals known as endorphins, are mixtures of two pentapeptides. Much research effort has been focussed on enkephalins and their analogs in search of analgesics with lesser drawbacks.
As a part of this research, the receptors to which opioids bind have been studied and characterized. The opioid receptors are the molecules on the cell surface which recognize the opioid and imitates its biological effects. The opioid receptors have been found to vary in their characteristics, and several types or classes of such receptors have been identified. The major types of proposed receptors are the mu, delta, and kappa receptors. All three receptors are involved in analgesia, but differ in other pharmacological effects. The mu receptors are associated with respiratory depression and inhibition of gastrointestinal transit. Kappa receptors mediate sedation. The delta receptors also mediate analgesfa, but do not seem to be associated with inhibition of gastrointestinal transit. Some recent evidence suggests that compounds selective for the delta receptors may not be subject to the dependence and tolerance problems generally associated with opiate analgesics that are non-selective as to receptor type or are selective for the mu receptor. Opioid compounds which bind to the opiate receptors are said to be "agonists" if they inhibit electrically stimulated output of neurotransmitters in tissues containing receptors and "antagonists" if they prevent such inhibition. Morphine is an agonist and naloxone is an antagonist.
The natural enkephalins, as stated, are a mixture of two pentapeptides, methionine enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) and leucine enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH). Much research has been directed toward identifying analogs of these compounds which are selective as to the types of opiate receptors to which they bind. See, e.g., Hruby and Gehrig, Medicinal Research Reviews, Vol. 9, No. 3, pp. 343-401 (1989).
One class of analogs of natural enkephalins has been identified with relatively high selectivity for delta-type opiate receptors. This type is based on substitutions for the second and fifth amino acid residues of the pentapeptides, with either cysteine or with D- or L-penicillamine (beta, beta-dimethylcysteine). A particularly noteworthy member of that class is [D-Pen.sup.2, D-Pen.sup.5 ] enkephalin, or "DPDPE," which has the D-Pen residues at the second and fifth positions joined by a disulfide link to make a cyclic molecule. This compound, and several analogs of it, are described in U.S. Pat. No. 4,518,711. The selectivity of DPDPE for the delta receptor is also described in Clark et al., Eur. Jour. Pharm., 128, pp. 303-304 (1986) among others. In addition, analogs of DPDPE have also been created, principally consisting of variations at the fourth residue (Phe), some of which have an even greater selectivity for the delta receptor. However, compounds of even greater selectivity for the delta receptors would still be useful, not only as candidates for clinical application, but also as research tools to further characterize the functioning of these biologically significant receptors.